The present invention relates to novel nucleotide analog amidates and esters, their pharmaceutically acceptable acid addition salts, a process for their production, and to their use. The nucleotides of the present invention exhibit antitumor/antineoplastic activity, a broad spectrum of antimicrobial activity and certain other desirable activities.
Compounds related to the nucleotide analogs of the present invention may be found in: U.S. Pat. Nos. 5,043,339, 5,108,994 and 5,166,198; EP 206 459; EP 253 412; EP 269 947; EP 270 885; EP 319 228; EP 343 133; EP 398 231; EP 404 296; EP 465 297; EP 468 119; EP 468 866; EP 479 640; EP 481 214; EP 494 370; EP 531 597; PCT/GB91/01171; PCT/US92/01020; PCT/US92/05208; WO 91/19721; Bronson et al, Bioorg Medicinal Chem Lett (1992) 2:685-690; Bronson et al, j Med Chem, (1989) 32:1457-1463; Bronson et al, Nucleotide Analogs as Antiviral Agents, ACS Symposium Series 401, J. C. Martin, Ed., p. 72-87, American Chemical Society, Washington, D.C. (1989); Colla, et al, J Med Chem (1983) 26:602-604; Curley, et al, Antiviral Res (1990) 14:345-356; De Clercq, et al, Nature, (1986) 323:464-467; Farrow, et al, J Med Chem (1990) 33:1400-1406; Farquhar, et al, J. Pharm Sci (1983) 72:324-325; Freed, et al, Biochem Pharmacol (1989) 19:3193-3198; Freeman, et al, J Med Chem (1992) 35:3192-3196; Gabrielsen, B., et al, Antiviral Res Suppl I (1992) 17:149; Gumport, et al, Proc Natl Acad Sci (1971) 2559-2563; Juodka, et al, Coll Czech Chem Commun (1974) 39:963-968; Kim, et al, Bioorg Medicinal Chem Lett (1992) 2:367-370; Kim, et al, Tet Lett (1992) 33:25-28; Kim, et al, J Med Chem (1990) 33:1207-1213; Kumar, et al, J Med Chem (1990) 33:2368-2375; McGuigan, et al, Antiviral Chem Chemother (1993) 4:97-101; McGuigan, et al, Antiviral Res (1991) 15:255-263; Rosenberg, et al, Coll Czech Chem Commun (1988) 53:2753-2777; Rosenberg, et al, Coll Czech Chem Commun (1988) 52:2792-2800; Rosenberg, et al, Coll Czech Chem Commun (1988) 52:2801-2808; Starrett, et al, Antiviral Res (1992) 19:267-273; Yu, et al, J Med Chem (1992) 35:2958-2969; Wolff-Kugel, et al, Tet Lett (1991) 32:6341-6344.
A characteristic of nucleotide analogs or nucleotides having a phosphonate or a phosphate group is the presence of one or two negative charges associated with the phosphorus group at physiologic pH. The charge associated with moieties such as phosphate or phosphonate groups is believed to generally limit bioavailability by limiting cell membrane permeation via passive diffusion (Liebman, et al, J. Biol. Chem., (1955) 216:823-830; Roll, et al, J Biol Chem, (1956) 220:439-444; Srivastava, et al, Bioorg Chem (1984) 12:118-129; Palu, et al, Antiviral Res (1991) 16:115-119; Sastry, et al, Mol Pharmacol (1992) 41:441-445). These compounds are often, therefore, given parenterally in order to enhance bioavailability by increasing serum or intracellular levels.
Other characteristics of nucleotide analogs that can limit their efficacy include unfavorable pharmacokinetic or pharmacodynamic properties, insufficient potency and/or unfavorable toxicity characteristics.
Studies were conducted to ameliorate one or more of the above-mentioned problems associated with nucleotide analog drugs. The present invention includes novel nucleotide analogs that are hydrolyzable in vivo. The nucleotide analogs can have improved bioavailability, improved pharmacokinetic or pharmacodynamic properties, enhanced potency and/or improved toxicity characteristics compared to the corresponding unmodified nucleotide analog. Methods to synthesize and use the compounds and methods to obtain and use antibodies that recognize the compounds are also disclosed.